NORD gratefully acknowledges Nguyen Anh Tuan Hoang (Patrick), PhD, MDCM Candidate, McGill University School of Medicine, and Yves Lacassie, MD, FACMG, Professor Emeritus, Department of Pediatrics LSUHSC, Head Division of Genetics 1986-2016 and Head Department of Genetics, Children’s Hospital New Orleans, for assistance in the preparation of this report.
Mosaic trisomy 22 is a rare chromosomal disorder in which chromosome 22 appears three times (trisomy) rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 22, whereas others have the normal chromosomal pair. Mosaic trisomy 22 appears more commonly in females. The range and severity of associated symptoms and findings may vary. The characteristic features of mosaic trisomy 22 typically include prenatal and postnatal growth failure or delay, asymmetrical development of the two sides of the body (hemidystrophy), congenital heart defects. While some patients with mosaic trisomy 22 have abnormal cognitive development, normal development has been documented for some children. The condition can be detected prenatally, through ultrasound (US), amniocentesis, or chorionic villus sampling (CVS). The condition is confirmed prenatally by fetal blood sampling or fetal skin biopsy. Postnatally, diagnosis of mosaic trisomy 22 is detected on blood and/or other tissue biopsy.
Mosaic trisomy 22 was first described by Schinzel in 1981. Since then, there have been about 20 reports on live born children with mosaic trisomy 22. It is speculated that children with mosaic trisomy 22 with minimal physical findings and normal development are under diagnosed. The condition appears to occur in females more frequently than in males (approximately 3 females: 2 males).
The symptoms and physical findings associated with Mosaic trisomy 22 may depend on the percentage and distribution of cells containing the extra 22nd chromosome. However, the disorder is often characterized by (1) growth and developmental delays, (2) asymmetric body development, and (3) congenital heart diseases.
Intrauterine growth restriction (IUGR) and postnatal growth failure were found in more than 70% patients with mosaic trisomy 22. While many affected children have developmental delay, up to 40% of all reported patients have normal developmental outcomes. It has been shown that there was no correlation between the percentage of trisomic cells and the severity of developmental delay.
In many affected individuals, there is asymmetric development of two sides of the body, causing the body to appear dissimilar from one side to the other (hemidystrophy). For example, one leg may appear shorter than the other. In addition, in many individuals with hemidystrophy, there is associated hearing loss affecting one ear (unilateral hearing impairment).
Patients with mosaic trisomy 22 often have congenital heart defects. Atrial septal defects and ventricular septal defects are the most common cardiac malformations for these patients. In the atrial septal defect, a “hole” in the wall separating the two top chambers (atrias) of the heart remains open after birth. This allows oxygen-rich blood to enter the oxygen-poor chamber (right atrium). On the other hand, the ventricular septal defect is a “hole” in the wall separating the two lower chambers (ventricles) of the heart. Intervention for these defects is determined by the size and severity of the defects.
Dysmorphic features are frequently seen in patients with mosaic trisomy 22. Some common presentations include skin fold of the upper eyelid covering the inner corner of the eye (epicanthic folds), characterized dents/dimples located near the front of the external ear (preauricular pits), and flat nasal bridge. Other features include underdeveloped middle phalanx of 5th finger (mesobrachydactyly or clinodactyly), abnormal palmar flexion creases, and kidney (renal) malformations. A few patients may have linear pigmentary changes along Blaschko lines.
A small subset of female patients may have defective development of the ovaries (ovarian dysgenesis, streak ovaries). The ovaries are essential glands for female reproductive cells (eggs) and certain female hormones. Therefore, ovarian dysgenesis may be associated with delayed or failed development of secondary sexual characteristics during puberty (e.g., breast development, the appearance of pubic hair, menstruation) and infertility.
There are 23 pairs of human chromosomes, or a total of 46 chromosomes. Mosaic trisomy 22 is characterized by an extra copy of the chromosome 22 (trisomy) in some of the body cell populations. This could be due to an error during the division of reproductive cells in one of the parents (mitotic nondisjunction) or during cellular division after fertilization (fetal mitosis). The disorder can also occur in association with uniparental disomy, an abnormality in which affected individuals have inherited both copies of a chromosomal pair from one parent, rather than one copy from each parent. The presence of the additional chromosome 22 in some groups of cells is responsible for the symptoms and physical findings of the disorder.
The diagnosis of trisomy mosaic 22 may be suggested before birth (prenatally) by specialized tests, such as ultrasound and amniocentesis. Fetal ultrasound is a non-invasive imaging technique that utilizes high-frequency sound waves to produce image of fetus in the uterus. Abnormal results during ultrasound may prompt to more invasive test such as amniocentesis. During amniocentesis, a sample amniotic fluid (AF) that surrounds the fetus is removed and analyzed. Chromosomal analysis of either AF or chorionic tissues can reveal the presence of mosaic trisomy 22. Karyotyping from AF is not sufficient to confirm a definitive diagnosis. Diagnostic confirmation may require fetal blood sampling or fetal skin biopsy (fetal fibroblast). It is important to note that normal ultrasound studies do not necessarily indicate the absence of impaired psychomotor development.
A diagnosis of mosaic trisomy 22 may also be made or confirmed after birth (postnatally) based upon clinical assessment through physical findings and chromosomal analysis. A normal karyotype on blood does not rule out the diagnosis of mosaicism, because the trisomic cells may be present only in some tissues. In addition, specialized testing may be conducted to detect or characterize abnormalities that may be associated with the disorder (e.g., cardiovascular defects, hearing impairment, renal abnormalities, ovarian dysgenesis, etc.).
The treatment of mosaic trisomy 22 is directed toward the specific problems that are apparent in each individual. Such treatment may require interdisciplinary efforts of health care professionals, including pediatricians, surgeons, cardiologists, ophthalmologists and other health care partners.
Some infants with mosaic trisomy 22 may require surgical repair for their congenital cardiac defects, certain craniofacial and other physical abnormalities associated with the disorder. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors. Patients with hearing loss may benefit from artificial devices (prostheses), such as specialized hearing aids.
Early intervention may be essential in ensuring that children with mosaic trisomy 22 reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families.
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